Mutations in the VHL gene in sporadic apparently congenital polycythemia
Abstract
The congenital polycythemic disorders with elevated erythropoietin (Epo) have been until recently an enigma, and abnormality in the hypoxia-sensing pathway has been hypothesized as a possible mechanism. The tumor suppressor von Hippel-Lindau (VHL) participates in the hypoxia-sensing pathway, as it binds to the proline-hydroxylated form of the hypoxia-inducible factor 1alpha (HIF-1alpha) and mediates its ubiquitination and proteosomal degradation. The loss of VHL function may result in the accumulation of HIF-1alpha and overproduction of HIF-1 downstream target genes including Epo. VHL syndrome is an autosomal dominant disorder predisposing to the development of tumors, due to inherited mutations in the VHL gene. Some rare patients with VHL syndrome have polycythemia, which has been attributed to Epo production by a tumor. It was recently found that homozygosity for the VHL Arg200Trp mutation is the cause of Chuvash polycythemia, an autosomal recessive polycythemic disorder characterized by elevated serum Epo and hypersensitivity of erythroid cells to Epo. We evaluated the role of VHL in 8 children with a history of polycythemia and an elevated serum Epo level and found 3 different germline VHL mutations in 4 of them. One child was homozygous for the Arg200Trp VHL mutation, and another compound heterozygous for the Arg200Trp and the Val130Leu mutations. Two children (siblings) were heterozygous for an Asp126Tyr mutation, one of them fulfilling some criteria of VHL syndrome. We propose that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum Epo concentration.
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Chuvash polycythemia is caused by a homozygous mutation in VHL at codon 200, R200W.
“It is caused by a homozygous mutation in the VHL tumor suppressor at codon 200, R200W”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [129]
Chuvash polycythemia is caused by a homozygous mutation in VHL at codon 200, R200W.
“It is caused by a homozygous mutation in the VHL tumor suppressor at codon 200, R200W”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [130]
Cites
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · see citing works
HIF-1 and mechanisms of hypoxia sensing
Semenza, G. L. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00194-0 · Cited by 1,267 · see citing works
Structure of an HIF-1α-pVHL Complex: Hydroxyproline Recognition in Signaling
Min, J.-H., Yang, H., Ivan, M., Gertler, F., Kaelin, W. G., & Pavletich, N. P. (2002) · Science · doi:10.1126/science.1073440 · Cited by 765 · see citing works
Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL
Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., & Jones, E. Y. (2002) · Nature · doi:10.1038/nature00767 · Cited by 751 · see citing works
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., et al. (2002) · Nature Genetics · doi:10.1038/ng1019 · Cited by 510 · see citing works
Self-citationClifford, S. C. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1029 · Cited by 373 · see citing works
Oxygen sensors and angiogenesis
Maxwell, P. H., & Ratcliffe, P. J. (2002) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.2001.0287 · Cited by 328 · see citing works
Genotype-phenotype correlation in von Hippel-Lindau syndrome
Friedrich, C. A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.7.763 · Cited by 149 · see citing works
Endemic Polycythemia in Russia: Mutation in the VHL Gene
Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., & Prchal, J. T. (2002) · Blood Cells, Molecules, and Diseases · doi:10.1006/bcmd.2002.0488 · Cited by 135 · see citing works
Self-citationSilva, J. D., Lacombe, C., Bruneval, P., Casadevall, N., Leporrier, M., Camilleri, J.-P., Bariety, J., Tambourin, P. E., & Varet, B. R. (1990) · Blood · doi:10.1182/blood.v75.3.577.577 · Cited by 129 · see citing works
Krieg, M., Marti, H. H., & Plate, K. H. (1998) · Blood · doi:10.1182/blood.v92.9.3388 · Cited by 126 · see citing works
Congenital Polycythemia in Chuvashia
Sergeyeva, A. S., Gordeuk, V. R., Tokarev, Y. N., Sokol, L., Prchal, J. F., & Prchal, J. T. (1997) · Blood · doi:10.1182/blood.v89.6.2148 · Cited by 117 · see citing works
Self-citationHuman Hematopoietic Progenitors Express Erythropoietin
Stopka, T., Živný, J., Stopková, P., et al. (1998) · Blood · doi:10.1182/blood.v91.10.3766 · Cited by 93 · see citing works
Erythroid progenitors differentiate and mature in response to endogenous erythropoietin
SATO, T. A., Maekawa, T., Watanabe, S., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9361 · Cited by 80 · see citing works
Wiesener, M. S., Seyfarth, M., Warnecke, C., Jürgensen, J. S., Rosenberger, C., Morgan, N. V., Maher, E. R., Frei, U. A., & Eckardt, K. (2002) · Blood · doi:10.1182/blood.v99.10.3562 · Cited by 80 · see citing works
“Benign erythrocytosis” and other familial and congenital polycythemias
Prchal, J. T., & Sokol, L. (1996) · European Journal Of Haematology · doi:10.1111/j.1600-0609.1996.tb01376.x · Cited by 58 · see citing works
Self-citationKrálovics, R., Sokol, L., & Prchal, J. T. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2886 · Cited by 55 · see citing works
Self-citationMolecular basis for polycythemia
Prchal, J. F., & Prchal, J. T. (1999) · Current Opinion in Hematology · doi:10.1097/00062752-199903000-00008 · Cited by 50 · see citing works
Self-citationRichard, S., Croisille, L., Yvart, J., Casadeval, N., Eschwège, P., Aghakhani, N., David, P., Gaudric, A., Scigalla, P., & Hermine, O. (2002) · Blood · doi:10.1182/blood.v99.10.3851 · Cited by 47 · see citing works
Erythropoietin titers in health and disease.
Erslev, A. J. (1991) · PubMed · Cited by 40 · see citing works
Horton, J. C., Harsh, G. R., Fisher, J. W., et al. (1991) · Neurology · doi:10.1212/wnl.41.5.753 · Cited by 32 · see citing works
Iyamu, W. E., Adunyah, S. E., Fasold, H., Horiuchi, K., Elford, H. L., Asakura, T., & Turner, E. (2000) · American Journal of Hematology · doi:10.1002/(sici)1096-8652(200004)63:4 · Cited by 27 · see citing works
Oetting, W. S., Gardner, J. M., Fryer, J. P., Ching, A., Durham‐Pierre, D., King, R. A., & Brilliant, M. H. (1998) · PubMed · doi:10.1002/(sici)1098-1004(1998)12:6 · Cited by 23 · see citing works
Královics, R., Sokol, L., Eh, B., et al. (1997) · PubMed · Cited by 17 · see citing works
Prchal, J. T. (1995) · Current Opinion in Hematology · doi:10.1097/00062752-199502020-00007 · Cited by 17 · see citing works
Self-citationKrieg, M., Marti, H. H., & Plate, K. H. (1998) · Blood · doi:10.1182/blood.v92.9.3388.421a09_3388_3393 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
Percy, M. J., Zhao, Q., Flores, A., Harrison, C., Lappin, T. R. J., Maxwell, P. H., McMullin, M. F., & Lee, F. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508423103 · Cited by 330 · see citing works
Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Butman, J. A., Jedlickova, K., Prchal, J. T., & Polyakova, L. A. (2004) · Blood · doi:10.1182/blood-2003-07-2535 · Cited by 273 · see citing works
Self-citationRegulation of adult erythropoiesis by prolyl hydroxylase domain proteins
Takeda, K., Aguila, H. L., Parikh, N. S., Li, X., Lamothe, K., Duan, L.-J., Takeda, H., Lee, F. S., & Fong, G.-H. (2008) · Blood · doi:10.1182/blood-2007-09-114561 · Cited by 263 · see citing works
Failure to prolyl hydroxylate hypoxia‐inducible factor α phenocopies VHL inactivation in vivo
Kim, W. Y., Safran, M., Buckley, M. R., Ebert, B. L., Glickman, J., Bosenberg, M., Regan, M., & Kaelin, W. G. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601300 · Cited by 235 · see citing works
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177 · see citing works
A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove
Percy, M. J., Furlow, P. W., Beer, P. A., Lappin, T. R. J., McMullin, M. F., & Lee, F. S. (2007) · Blood · doi:10.1182/blood-2007-04-084434 · Cited by 155 · see citing works
Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis
Percy, M. J., Beer, P. A., Campbell, G., Dekker, A. W., Green, A. R., Oscier, D., Rainey, M. G., van Wijk, R., Wood, M., Lappin, T. R. J., et al. (2008) · Blood · doi:10.1182/blood-2008-02-137703 · Cited by 127 · see citing works
Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia
Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., & Prchal, J. T. (2003) · The American Journal of Human Genetics · doi:10.1086/377108 · Cited by 106 · see citing works
Self-citationPerrotta, S., Nobili, B., Ferraro, M., Migliaccio, C., Borriello, A., Cucciolla, V., Martinelli, V., Rossi, F., Punzo, F., Cirillo, P., et al. (2006) · Blood · doi:10.1182/blood-2005-06-2422 · Cited by 93 · see citing works
Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry
Percy, M. J., McMullin, M. F., Jowitt, S. N., Potter, M., Treacy, M., Watson, W. H., & Lappin, T. R. J. (2003) · Blood · doi:10.1182/blood-2002-10-3246 · Cited by 90 · see citing works
The worldwide distribution of the VHL 598C>T mutation indicates a single founding event
Liu, E., Percy, M. J., Amos, C. I., Guan, Y., Shete, S., Stockton, D. W., McMullin, M. F., Polyakova, L. A., Ang, S. O., Pastore, Y. D., et al. (2004) · Blood · doi:10.1182/blood-2003-07-2550 · Cited by 66 · see citing works
Erythrocytosis and the Chuvash von Hippel-Lindau mutation
Percy, M. J., Beard, M. E. J., Carter, C., & Thein, S. L. (2003) · British Journal of Haematology · doi:10.1046/j.1365-2141.2003.04631.x · Cited by 8 · see citing works
- Authors
- Pastore, Y. D., Jelinek, J., Ang, S., Guan, Y., Liu, E., Jedlickova, K., Krishnamurti, L., & Prchal, J. T.
- Affiliations
- University of Minnesota (US)
- From the Texas Children's Cancer Center and Hematology Service, Houston; Baylor College of Medicine and Veterans Administration Hospital, Houston, TX; and University of Minnesota, Minneapolis.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2003-02-15
- Volume
- 101
- Issue
- 4
- Pages
- 1591-1595
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2000596340
- Cited by
- 136
- References
- 28
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 9 · 2012: 4
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL5007-08, R01HL066333, R01HL66333-01)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Keywords
- VHL gene, von Hippel-Lindau disease, erythropoietin, hypoxia-inducible factor-1α, germline mutations, compound heterozygosity, tumor suppressor
- MeSH terms
- Adolescent, Adult, Arginine, Aspartic Acid, Base Sequence, Child, Child, Preschool, DNA Mutational Analysis, Erythropoietin, Female, Heterozygote, Homozygote, Humans, Leucine, Ligases, Male, Mutation, Pedigree, Polycythemia, Tryptophan, Tyrosine, Valine, Erythroid Precursor Cells, Sequence Analysis, DNA, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
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